Medullary thyroid carcinoma (MTC) constitutes around 5% of all thyroid cancers. It accounts for as much as 13% of all thyroid cancer-related deaths. MTC usually arises from parafollicular C-cells that normally secrete a number of peptide hormones such as calcitonin, serotonin, and vasoactive intestinal peptide; thus, it is widely accepted as a neuroendocrine tumor. Both sporadic and familial forms are seen, the sporadic form being responsible for 70% of the cases and familial form for 10-20% of the cases. Here, we present a case report of two patients with sporadic MTC. The first patient underwent total thyroidectomy with central compartment neck dissection and right lateral neck dissection, and also in the second patient, total thyroidectomy with central compartment neck dissection was done. Final histopathology came out to be medullary carcinoma of the thyroid. Postoperative serum calcitonin at 2 months following the surgery came out to be normal. Both the patients are on regular follow-up, and there has been no recurrence. Genetic screening and the evaluation of familial syndromes should always be considered in preoperative work-up in MTC patients. Early diagnosis offers a higher likelihood of cure and long-term survival. Total thyroidectomy plus central compartment neck dissection is the mainstay of treatment. All patients must be kept on regular follow-up to avoid recurrence.

Medullary thyroid carcinoma (MTC) constitutes around 5% of all thyroid cancers. [1] It accounts for as much as 13% of all thyroid cancer-related deaths. [2],[3] MTC usually arises from parafollicular C-cells that normally secrete a number of peptide hormones such as calcitonin, serotonin, and vasoactive intestinal peptide; thus, it is widely accepted as a neuroendocrine tumor. Both sporadic and familial forms are seen, the sporadic form being responsible for 70% of the cases and familial form for 10-20% of the cases. The prognosis of MTC is worse as compared to differentiated thyroid cancers, with a 10-year survival rate of 95.6% in cases restricted to the thyroid gland, but only 40% for those presenting with metastasis. [4] Here, we present the case reports of two patients with sporadic MTC.

Case Reports

Case 1

A 19-year-old female presented with progressively increasing midline swelling for 2 months. Neck examination revealed 3 cm × 2 cm × 2 cm swelling on the right side of the neck, extending from midline to the anterior border of sternocleidomastoid, which was 2 cm below the hyoid and up to 3 cm from the suprasternal notch. On palpation, it was firm and mobile. She also had enlarged lymph nodes in the right level II and level III, each measuring 1 cm × 1 cm [Figure 1]. She had raised levels of thyroid-stimulating hormone being 9.92 μIU/ml with normal levels of free T3 (2.38 pg/ml) and free T4 (1.18 ng/ml). Serum calcitonin was raised 100 times above the normal level being 1404 pg/ml. Ultrasonography of the neck showed the presence of two hypoechoic lesions in the right lobe of thyroid with the specifications of macrocalcifications as well as both central and peripheral vascularity. Fine-needle aspiration cytology (FNAC) of the right lobe of thyroid was suggestive of medullary carcinoma of thyroid. Moreover, FNAC from cervical nodes revealed metastasis of medullary carcinoma of thyroid. Computed tomography (CT) neck was also suggestive of two nodules in the right lobe of thyroid and metastatic lymphadenopathy [Figure 2].

Figure 1: A young female with midline neck swelling more on the right, with palpable level 2 and level 3 neck nodes

The second patient was a 49-year-old female with swelling in the midline of the neck for 1 year with no other associated complaints. Clinical examination showed a midline firm neck swelling about 3 cm × 2 cm × 2 cm moving with deglutition. Cervical lymph nodes were not palpable [Figure 3]. Ultrasonography of the neck revealed a dominant hypoechoic nodule in the mid part of the left lobe of thyroid with subcentimetric hypoechoic lesions in rest of the left lobe and right lobe of thyroid. FNAC was performed which was suggestive of the features of medullary carcinoma of thyroid. Serum calcitonin was 215 pg/ml, and thyroid function tests were within normal limits. Contrast-enhanced CT (CECT) neck also revealed heterogeneous enhancement in the left lobe of thyroid [Figure 4].

There was no past history of thyroiditis, radiation exposure, or a family history of MTC. Both the patients underwent laboratory evaluation of serum calcium and 24 h urinary metanephrines which came out to be normal.

The first patient underwent total thyroidectomy with central compartment neck dissection and the right lateral neck dissection [Figure 5], and also in the second patient, total thyroidectomy with central compartment neck dissection was performed [Figure 6]. Final histopathology showed nests and sheets of cells with moderate-to-abundant cytoplasm, eccentrically placed nuclei surrounded by dense pink homogeneous material (amyloid), and the tumor was limited to thyroid capsule. Postoperative serum calcitonin at 6 months following the surgery came out to be 2 pg/ml in the first patient and 1 pg/ml in the second case. Both the patients are on regular follow-up, and there has been no recurrence.

Figure 5: Specimen showing total thyroidectomy with neck dissection in the first patient

MTC was identified as a distinct clinical and pathological entity in 1959. [5] Sporadic MTC usually presents in the fifth or sixth decade and has a slight female preponderance. Hereditary MTC is, however, more common in the younger age group, of which multiple endocrine neoplasia type 2A (MEN 2A) and familial thyroid cancer usually arise when patients are in their 30s, and MEN 2B typically presents in those <20 years of age. Hereditary forms are transmitted as an autosomal dominant trait either alone as familial MTC (FMTC) or as part of MEN 2A or 2B. [6],[7] Germline mutations of the RET proto-oncogene (RET) found on chromosome 10q11 are responsible for FMTC s and may be present in more than 95% of the hereditary MTCs and about 25% of the sporadic MTCs. [8]

The most common presentation of sporadic MTC is a painless solitary thyroid nodule, and multifocality and bilaterality are the features of the hereditary forms. [9] Cervical lymph node metastasis is approximately found in 50% of the cases at the time of diagnosis, whereas distant metastases are present in 10% of the cases; [10] higher incidence being those with large tumor size or multifocal tumors. [11] In our study also, both the females presented with multiple hypoechoic nodules, but cervical metastasis was found only in the first patient. Being a neuroendocrine tumor, in some of the cases, excess calcitonin secretion may cause symptoms such as flushing and diarrhea. [12] In addition, some of the patients may even present with systemic manifestations due to the secretion of several peptides and substances, including vasoactive intestinal peptide, chromogranin A, bombesin, neurotensin, carcinoembryonic antigen (CEA), somatostatin, and adrenocorticotropic hormone. However, both of our patients did not have any of these symptoms.

Serum calcitonin levels serve as a specific tumor marker with a high sensitivity rate for MTC diagnosis. [13],[14] It is also helpful in detecting recurrence after surgery. Although a lot of physiologic and pathologic conditions such as physical activity, hypergastrinemia, hypercalcemia, renal insufficiency, and proton pump inhibitory drugs may even be related to hypercalcitoninemia, it is seen that only up to 40% of all cases with raised serum calcitonin levels in the presence of a thyroid nodule actually have MTC. [15] Thus, according to the American Thyroid Association, it is not routinely recommended and hence preoperative normal calcitonin value always cannot exclude the diagnosis of MTC. [16] Another biomarker, CEA, is also produced by the neoplastic C-cells, and it has been useful in predicting the prognosis of MTC patients, more importantly when preoperative serum calcitonin values are negative. [17] CEA may be found in >50% of the MTC patients, and levels above 30 ng/ml strongly indicate a poor prognosis. [18] It is also seen that CEA values more than 100 ng/mL are found to be associated with extensive lymph node involvement and distant metastasis. [16] Here, both of our patients had significantly raised levels of serum calcitonin which regressed to baseline following the surgery, but CEA was not done.

Neck ultrasound should be performed as the traditional approach to thyroid nodules. Although MTC has no classical feature on ultrasound, it can be helpful to show the nodule characteristics, enlarged lymph nodes, if any, and to guide FNAC from the suspicious nodules. FNAC is usually the first line of investigation for diagnosing thyroid nodules. In both of our cases, classical features of MTC in FNAC were seen which included plasmacytoid appearance of cells and multiple spindle-shaped cells with the presence of amyloid.

In both the cases, MTC was of sporadic type on account of the absence of family history. Pheochromocytoma was ruled out on the basis of normal abdominal CT scan, normal plasma catecholamine levels, and excretion of metanephrine and nor-metanephrine in a urine sample collected after 24 h.

It is recommended that we should look for RET germline mutations in all cases that presented with MTC and/or pheochromocytoma and in at-risk family members from MEN 2 genealogies. [19] In our first case, the patient underwent genetic testing for detecting mutations in RET proto-oncogene, but it came out to be negative. This was important as the patient was a young 19-year-old female with extensive disease, and the absence of mutation ruled out the possibility of other associated tumors and hence, further in future, we need not follow up her for other neuroendocrine tumors. Since the second patient was a middle-aged female with no cervical metastasis, we did not go ahead with genetic testing in her.

Total thyroidectomy along with central compartment neck dissection is the treatment of choice for the patients with medullary carcinoma of thyroid. The incidence of central neck metastasis can be as high as 81% in patients with palpable tumors [20] and thus, central compartment neck dissection provides a better survival and cure rate than total thyroidectomy alone. [21] The role of routine lateral neck dissection in treating patients with MTC is less clear. Ipsilateral lateral nodal metastases may be present in 14-80% of the patients, [11],[20] and contralateral lateral nodal metastases have been described in 19-49% of the patients. [20],[22] Since there is a huge risk of neck metastasis, even in tumors <1 cm, few surgeons do recommend bilateral lateral neck dissection in all patients with MTC. [20],[22] As we all know that bilateral neck dissection is associated with a lot of complications, many surgeons advise a conservative approach to the lateral neck, especially in case when the primary tumor is <1 cm. And hence, ipsilateral neck dissection becomes necessary when enlarged/suspicious lymphadenopathy is detected by ultrasonography or physical examination, central compartment lymph nodes are involved, or the primary tumor size is larger than 1 cm.

Although even after diligent surgical removal of all neck lymph nodes, it is seen that just 32% of the patients with nodal disease at the time of surgery have significantly decreased calcitonin levels postoperatively. [22]

All those patients who present with disease limited to the thyroid gland without neck node involvement tend to have a low recurrence rate and rarely die from their disease. [23] However, since a lot of patients with MTC have nodal disease at the time of presentation, they are at a greater risk for developing recurrent or persistent disease. Thus, they have to be on a strict postoperative follow-up and monitoring. The postoperative follow-up should begin 2-3 months after operation and it is based on serum calcitonin and CEA levels. Patients with undetectable calcitonin levels postoperatively are usually followed with yearly measurements of serum calcitonin and CEA. In addition, ultrasound of the neck can also be done, but appears to have no added advantage. In case of patients with elevated levels of serum markers, ultrasound of the neck or CT/magnetic resonance imaging can be done. Although thyroid hormone replacement is required after a total thyroidectomy, thyroid-stimulating hormone suppression is not needed in patients with MTC. Annual screening becomes necessary for all patients with hereditary disease to look for the development of pheochromocytoma and hyperparathyroidism.

The prognosis for patients with MTC seems good with a 10-year survival rate for patients with MTC being 75-85%. [24],[25],[26] About 50% of the patients with MTC have disease restricted to the thyroid gland, and have a 10-year survival rate of 95.6%. [25] Approximately, one-third of the patients present with locally invasive tumors or with metastasis to the regional lymph nodes. The survival rate of patients with regional disease is 75.5%. Distant metastases may be seen in 13% of the patients at the initial diagnosis and have a poor prognosis, with a 10-year survival rate of only 40%. Prognosis is better in patients with MEN 2A as compared to sporadic MTC, as sporadic carcinoma is usually diagnosed late when the disease is pretty advanced. In addition, FMTC has a better survival rate and MEN 2B seems to have the worst prognosis (Bergholm etal., 1990, Grauer etal., 1990, Samaan etal., 1988, and Nguyen etal., 1992). Early diagnosis has a chance of offering higher cure rate.

Radio-active iodine therapy seems to have no role in MTC as the tumor originates from parafollicular C-cells which do not accumulate iodine. This has been proved in a study by Meijer etal. where they found no significant additional value of radioactive iodine which was found in the management of all MTC subtypes. [27] Both radiation therapy and conventional chemotherapy have limited place in the treatment of patients with MTC. Vandetanib and cabozantinib are the newer tyrosine kinase inhibitors which have been approved by the US Food and Drug Administration for the treatment of progressive and metastatic MTC. [28],[29]

Conclusion

MTC being an uncommon and a rare thyroid malignancy, its management is different than that for differentiated thyroid cancers. Genetic screening and the evaluation of familial syndromes should always be considered in preoperative work-up in MTC patients. Early diagnosis offers a higher likelihood of cure and long-term survival. Total thyroidectomy plus central compartment neck dissection is the mainstay of treatment. All patients must be kept on regular follow-up to avoid recurrence.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.